The long term objective of this research is to produce effective vaccines against the most common respiratory paramxyoviruses of childhood: human parainfiuenza virus types 1, 3 and respiratory syncytial virus (RSV). Despite the epidemiologic importance of these viruses, effective vaccines do not exist. Challenges facing the development of paramyxovirus vaccines include concerns regarding safety and the need to elicit durable and effective humoral and cellular immune responses. The murine parainfluenza virus (PIV) type 1 (Sendai virus) is an excellent candidate respiratory virus vaccine backbone as it has elicited protection against human PIV type 1 (hPIVl1) in a non-human primate study and has successfully entered Phase I human safety trials. Additionally, recombinant Sendal virus has been shown to elicit protective immune responses against alternate targets (RSV), thus establishing Sendai virus as a vaccine vector for other Paramyxoviruses. Specific Aims in this Project are focused on: AIM 1: Evaluating the tolerability of increasing doses of intranasal Sendai virus among seropositive and then seronegative children. AIM 2: Characterizing hPIV1-specific antibody responses elicited by intranasal Sendai virus among adult and pediatric recipients. AIM 3: Determining whether recombinant SV vaccines can protect non-human primates from respiratory virus challenge, in anticipation of human studies. This project examining Sendal virus as a novel vaccine candidate for hPIV1 and as a backbone for related paramyxoviral antigens is a fundamental component of this Program and an essential bridge between the laboratory and clinical elements of vaccine design and evaluation. The pediatric study (Aim 1) will identify the highest tolerated dose of intranasal SV among seronegative toddlers, essential to conduct future placebocontrolled studies with this single dose. Recombinant SV prepared and characterized in Projects 1 and 2, will be tested here (Aim 3) for safety and protection in non-human primates, an essential precursor to clinical studies. Accordingly, this Project represents the culmination of work across all Projects, focused on developing effective pediatric vaccines for the most common respiratory viruses of childhood.